PATHOPHYSIOLOGY

Edosa Amante (BSc, MPH, PhD Candidate)

CHAPTER 3
INFLAMMATION
2

10/27/2024
 INFLAMMATION
 Definition: Inflammation is a local response (reaction) of living

vascularized tissues to endogenous and exogenous stimuli.

 The term is derived from the Latin "inflammare“ meaning to burn.

 Inflammation is fundamentally destined to localize and eliminate the

causative agent and to limit tissue injury.

 Thus, inflammation is a physiologic (protective) response to injury.

3
 Causes:
Causes of inflammation are apparently causes of diseases such as

Physical agents - mechanical injuries, alteration in temperatures and pressure,

radiation injuries.

Chemical agents- including the ever-increasing lists of drugs and toxins.

Biologic agents (infectious)- bacteria, viruses, fungi, parasites

 Immunologic disorders- hypersensitivity reactions, autoimmunity,

immunodeficiency states etc

Genetic/metabolic disorders- examples gout, diabetes mellitus

 Inflammatory lesion are usually indicated by the suffix 'itis’. 4

 CLASSIFICATION OF INFLAMMATION
ACUTE INFLAMMATION

 Acute inflammation is an immediate and early response

 It is relatively for short duration, lasting for minutes, several hours, or

a few days.

 Characterized by the exudation of fluids and plasma proteins and the

emigration of predominantly neutrophilic leukocytes to the site of

injury.
5
 THE FIVE CARDINAL SIGNS OF ACUTE INFLAMMATION
Redness:- which is due to dilation of small blood vessels.

Heat: - results from increased blood flow (hyperemia)

Swelling (tumor):- is due to the accumulation of fluid in the extravascular space

which, in turn, is due to increased vascular permeability

Pain:- partly results from the stretching & destruction of tissues.

Chemicals like bradykinin, serotonin…

 Loss of function: inflamed area is inhibited by pain while severe swelling may

also physically immobilize the tissue.

6
 EVENTS OF ACUTE INFLAMMATION:
Acute inflammation is categorized into early vascular and late cellular
responses.
1) The Vascular response has the following steps:
a) Immediate (momentary) vasoconstriction in seconds due to neurogenic or
chemical stimuli.
b) Vasodilatation of arterioles and venules resulting in increased blood flow.
c) after a slowing of blood flow & stasis due to increased vascular permeability
that is most remarkably seen in the post-capillary venules.

Stasis result exudate, edema

7
2) Cellular response
…
The cellular response has the following stages:
A. Migration, rolling, pavement, & adhesion of leukocytes
B. Transmigration of leukocytes
C. Chemotaxis
D. Phagocytosis

8
A) MIGRATION, ROLLING, PAVEMENTING, AND ADHESION OF LEUKOCYTES
Migration is a peripheral positioning of white cells along the endothelial
cells.

 Subsequently, rows of leukocytes tumble slowly along the endothelium in

a process known as rolling

In time, the endothelium can be virtually lined by white cells. This

appearance is called pavementing

Thereafter, the binding of leukocytes with endothelial cells is facilitated

by cell adhesion molecules such as selectins, immunoglobulins, integrins ,

etc which result in adhesion of leukocytes with the endothelium. 10/27/2024 9
B). Transmigration of leukocytes

Leukocytes escape from venules and small veins but only

occasionally from capillaries.

The movement of leukocytes by extending pseudopodia

through the
vascular wall occurs by a process called diapedesis.

10
C). Chemotaxis:

 A unidirectional attraction of leukocytes from vascular

channels towards the site of inflammation within the tissue

space guided by chemical gradients (including bacteria and
cellular debris)

 All granulocytes, monocytes, and to a lesser extent

lymphocytes respond to chemotactic stimuli.

11
D) Phagocytosis

Phagocytosis is the process of engulfment and internalization

by specialized cells of particulate material, which includes

invading microorganisms, damaged cells, and tissue debris

 These phagocytic cells include polymorphonuclear

leukocytes (particularly neutrophils), monocytes, and tissue

macrophages.

12
Phagocytosis involves three distinct but
interrelated steps.
1). Recognition and attachment
2). Engulfment
3) Killing or degradation

13
 IV. CHEMICAL MEDIATORS
 Inflammatory mediators are the substances that initiate and regulate
inflammatory reactions.

 Chemical mediators account for the events of inflammation.

Mediators originate from either – plasma or cells

 Plasma - These are present in precursor forms that must be activated by a

series of proteolytic cleavage to acquire biological properties

 Cells – present in intracellular granules that need to be secreted (e.g.

Histamine in mast cells) or synthesized denovo in response to stimulus (e.g.
Prostaglandins, cytokines)
 CHEMICAL MEDIATORS OF INFLAMMATION

Inflammation has the following sequence:

Cell injury => Chemical mediators => Acute inflammation

(the vascular & cellular events).

CHEMICAL MEDIATORS
 CHEMICAL MEDIATORS
Mediators perform activity by –

 Mostly by binding to receptors on target cells

 Direct enzymatic activity e.g. Lysosomal proteases

 Mediate oxidative damage e.g. reactive oxygen species & nitrogen

intermediates

Mediators can act on –

 One or few target cells

 Can have diverse targets

 Have different effect on different cell types

 CHEMICAL MEDIATORS
Once activated & released from the cell the mediators are short
lived.
They either –
 Quickly decay e.g. Arachidonic acid metabolites

 Inactivated by enzymes e.g. kininase inactivates Bradykinin

 Scavenged e.g. antioxidants scavenge toxic oxygen metabolites

 Inhibited e.g. complement regulatory proteins breakup & degrade

activated complement components
 CHEMICAL MEDIATORS
Vasoactive amines

First mediators to be released during inflammation are -

• Histamine
• Serotonin
 CHEMICAL MEDIATORS
HISTAMINE and serotonin

 Dilation of arterioles ( but constriction of large arterioles )

 Increased permeability of veinules

 Principle mediator of immediate transient phase of increased

vascular permeability

 Acts on microcirculation mainly via binding to H1 receptor on

endothelial cells
 CELL-DERIVED CHEMICAL
Cellular mediator Cell origin Function

Histamine Mast scells, basophiles Vascular leakage & platelets

Serotonin Platelet Vascular leakage

Prostaglandins All leukocytes Vasodilatation, pain, fever

Liposomal enzymes Neutrophiles Bacterial & tissue destruction
macrophages

Leukotriene All leukocytes LB4 Chemoattractant LC4, LCD4, & LE4 Broncho
and vasoconstriction

Platelet activating factor All leukocytes Bronchoconstriction and WBC priming

Activated oxygen species All leukocytes Endothelial and tissue damage

Nitric oxide Macrophages Leukocyte activation

Cytokines Lymphocytes, macrophages Leukocyte activation

EFFECTS OF ACUTE INFLAMMATION:
A. Beneficial effects

 Dilution of toxins:

 Protective antibodies:

 Fibrin formation:

 Plasma mediator systems provisions:

 Cell nutrition:

 Promotion of immunity:

22
B. Harmful effects

 Tissue destruction; Inflammation may result in tissue necrosis and

the tissue necrosis may, in turn, incite inflammation.

 Swelling: may have serious mechanical effects at certain locations.

 Inappropriate response: The inflammatory seen in hypersensitivity

reactions is inappropriate (i.e. exaggerated).

23
 COURSE OF ACUTE INFLAMMATION
Acute inflammation may end up in:

 Resolution: i.e. complete restitution of normal structure and function

of the tissue, eg. lobar pneumonia.

 Healing by fibrosis (scar formation).

 Abscess formation; if it is left untouched, it may result in abscesses

Progress to chronic inflammation

24
 CHRONIC INFLAMMATION
 Definition: it is a prolonged inflammatory process (weeks or

months) where an active inflammation, tissue destruction and

attempts at repair are proceeding simultaneously.

 Causes of chronic inflammation:

1. Persistent infections: intracellular infection such as tuberculosis,

leprosy, certain fungi etc are low toxicity and evoke delayed
hypersensitivity reactions
2. Prolonged exposure to nondegradable but partially toxic substances:
25

like atherosclerosis, silica, asbestos.

3. Progression from acute inflammation: Acute inflammation
almost always progresses to chronic inflammation
following:
4. Autoimmunity: such as rheumatoid arthritis.
 MORPHOLOGY:
Cells of chronic inflammation:

 Monocytes and Macrophages are the primary cells in

chronic inflammation.

 T- Lymphocytes

B-lymphocytes and Plasma cell

27
 Thus, the overall differentiation points between acute and chronic inflammations

include:

Characteristics Acute inflammation Chronic inflammation

Duration Short Relatively long

Pattern Stereotyped Varied

Predominant cel Neutrophils/Lymphocyt Macrophages,/plasma

es cells
Tissue destruction Mild to moderate Marked

Fibrosis Absent Present

Inflammatory reaction Exudative Productive

28
 The systemic effects of inflammation include:

a. Fever
b. Endocrine & metabolic responses
c. Autonomic responses
d. Behavioral responses
e. Leukocytosis
f. Leukopenia
g. Weight loss
29
 CHAPTER- FOUR
HEALING
 The word healing refers to the body’s replacement of destroyed tissue by living
tissue.

 Processes of healing

The healing process involves two distinct processes:

 Regeneration- complete restitution of lost or damaged tissue with similar tissue.

 Repair- regeneration & scar formation by the deposition of collagen (fibrosis) 30

a. Healing by regeneration
regeneration involves two processes
1. Proliferation of surviving cells to replace lost tissue
2. Migration of surviving cells into the vacant space.

b. Repair (Healing by connective tissue):- wounds that extend

through the basement membrane to the connective tissue lead to the
formation of granulation tissue and eventual scarring.

31
HEALING …

32
 PATTERN OF WOUND HEALING
 Two patterns depending on the amount of tissue damage:

1. Healing by first intention (Primary union)

 Healing of clean surgical wound

 Minimal tissue loss

 1st-day neutrophils, 3rd-day macrophages, by day 5 incision is

replaced by granulating tissue.

 Tensile strength of the wound increases thereafter, but it may take

months for the wounded area to obtain its maximal strength. 33

First intention healing 10/27/2024 34
2. HEALING BY SECOND INTENTION (SECONDARY UNION)
 More extensive loss of cells and tissue, such as infarction, inflammatory ulceration,
abscess formation.

 Regeneration of parenchymal cells cannot completely reconstitute the original

architecture.
Secondary healing differs from primary healing in several respects:

1. Inevitably, large tissue defects, more fibrin and more necrotic debris and exudate that
must be removed, more intense inflammatory rxn.

2. Much larger amounts of granulation tissue are formed.

3. Wound contraction, which occurs in large surface wounds.

4. Takes much longer than when it occurs by first intention.

Second intention healing
 FACTORS THAT INFLUENCE WOUND HEALING

Local Factors
Type, size, and location of the
wound
Vascular supply
Infection
Movement

37
 COMPLICATIONS IN CUTANEOUS WOUND HEALING
 Complications in wound healing can arise from abnormalities in any of the basic components
of the repair process.
 (1) Deficient scar formation,

 (2) Excessive formation of the repair components, and

 (3) Formation of contractures.

• Inadequate formation of granulation tissue or assembly of a scar can lead to two types of
complications:
 1.wound dehiscence and

 2. ulceration

• Dehiscence or rupture of a wound is most common after abdominal surgery and is due to
38
increased abdominal pressure.
•The accumulation of excessive amounts of collagen may give

rise to a raised scar known as a hypertrophic scar;

•if the scar tissue grows beyond the boundaries of the original

wound and does not regress, it is called a keloid.

39
HYPERTROPHIC SCAR

40
KELOID
KELOID

42
CONTRACTURES (CICATRISATION)

WOUND HEALING etsetamir@gmail.com 43

BURN SCARS

44
Fracture Repair
 Fracture Repair
 Step 1: Hematoma formation
A. Immediately after the fracture, extensive bleeding occurs. Over a period of
several hours, a large blood clot, or hematoma, develops.
B. Bone cells at the site become deprived of nutrients and die. The site
becomes swollen, painful, and inflamed.
• Step 2: Fibro-cartilaginous callus formation
A. Granulation tissue is formed as the hematoma is infiltrated by capillaries and
macrophages, which begin to clean up the debris.
B. Some fibroblasts produce collagen fibers that span the break , while others
differentiate into chondroblasts and begin secreting cartilage matrix.
C.Osteoblasts begin forming spongy bone.
D. This entire structure is known as a fibro cartilaginous callus and it splints the
broken bone.
 Step 3: Boney callus formation
A. Bone trabeculae increase in number fibro cartilaginous callus
bony callus of spongy bone
B. Typically takes about 6-8 weeks for this to occur.

• Step 4: Bone remodeling

A. During the next several months, the bony callus is continually
remodeled.
B. Osteoclasts work to remove the temporary supportive structures
• Osteoblasts rebuild the compact bone and reconstruct the bone
so it returns to its original shape/structure.